HUT67086A - Imidazo-pyridine derivatives pharmaceutical compositions containing them and process for their production - Google Patents

Description

The present invention relates to novel imidazopyridine derivatives of formula (I): wherein:

R is a group of formula (I),

R ¹ is A substituted alkenyl or alkynyl group containing up to 6 carbon atoms,

R ² is H, -COOH, -COOA, -CN, -NO 2, -NHCOR ⁵ , -NHSO ² R ⁵ or -5-tetrazolyl,

R ³ is R ⁵ -CO-alkyl, Ar-CO-alkyl, Het-CO-alkyl or Het-alkyl, the alkyl of which is in each case C 1-6,

R ⁴ is hydrogen or halogen,

R ⁵ is C 1 -C 6 alkyl, in which one or more hydrogen atoms may be replaced by fluorine atoms,

X is absent or represents -NH-CO-, -CO-NH-, -O-CH (COOH), -NH-CH (COOH), -NA-CH (COOH), -CH = C (COOH), -CH = C (CN) or -CH-C- (-5-tetrazolyl) -,

Y is oxygen or sulfur,

A is C 1-6 alkyl,

Ar is unsubstituted or phenyl substituted with -R ⁵ , -O ⁵ R ⁵ , -COOH, -COOA, -CN, -NO 2, -NH 2, -NHCOR ⁵ , -NHSO ² R ⁵ or -5-tetrazolyl,

Seven is a five- or six-membered heteroaromatic group containing from 1 to 3 nitrogen, oxygen and / or sulfur atoms, which may be optionally fused to a benzene or pyridine ring, and

Hal is fluorine, chlorine, bromine or iodine and salts thereof.

Similar compounds are described in European Patent Application A2-0400 974.

It is an object of the present invention to provide new compounds having valuable properties, in particular those useful in the preparation of medicaments.

It has now been found that the compounds of formula I and their salts have very valuable pharmacological effects and are well tolerated by the patient. In particular, they have angiotensin II antagonist properties and are therefore useful in the treatment of angiotensin II-dependent hypertension, aldosteronism, heart failure, and intraocular pressure, and in the treatment of central nervous system disorders, and in the treatment of blood vessels and cardiac hypertrophy and hyperplasia. angina pectoris, myocardial infarction, stroke, recurrent narrowing following angioplasty or by-pass surgery, arteriosclerosis, increased intraocular pressure, glaucoma, spotty degeneration, hyperuricemia (uric acid release in the blood), kidney failure angiotensin II mediated female genital disorders, sensory disorders such as dementia, amnesia, memory disorders, anxiety, depression and / or epilepsy.

These effects can be assayed by standard in vitro or in vivo methods, such as those described in U.S. Patent Nos. 4,880,804 and 5,036,048, PCT Patent Publication No. WO 91/14367, and A.T. Chiu et al., J. Pharmacol. Exp. Therap. 250: 867-874 (1989) and P.C. Wong et al., 1990, 252, 719-725, the method disclosed in the latter is an in vivo study in rats.

The compounds of formula I are useful as pharmaceutical active ingredients in human and veterinary medicine, in particular for the prophylaxis and / or treatment of heart, cardiovascular and vascular diseases, in particular hypertension, heart failure and hyperaldosteronism.

The present invention relates to compounds of the formula I and their salts and to processes for the preparation thereof, which process comprises: (a) reacting a compound of the formula II wherein E is a chlorine, bromine or iodine atom, or hydroxyl swept to a free or reactive functional group; and

R ² and X are reacted with a compound of formula (III) wherein R is a compound of formula (I) or (b) a compound of formula (IV) wherein

R ⁶ is R 1 -CO- or hydrogen, and

^R7 is hydrogen (when R ⁶ is R j-CO) or ^R1 -CO (if R ⁶ is hydrogen), and

R ¹ , R ² , R ³ , R ⁴ , X and Y are treated with the cyclizing agent represented by formula (I), or (c) for the preparation of compounds of formula (I) wherein

X is -NH-CO- or -CO-NH-, a compound of formula (V): wherein: • ♦ ·

- 5 X ¹ is -NH ₂ or -COOH,

R is a compound of formula (I) or a reactive derivative of these compounds with a compound of formula (VI): wherein

X ² is -COOH (when X ¹ is -NH ₂ ), or

-NH ₂ (when X ¹ is -COOH), and

R ² is as defined for formula (I) or a reactive derivative thereof, or (d) a compound of formula VII wherein R ¹ , R ² , R ⁴ , X and Y are as defined for formula (I) reacting with a compound of formula VIII wherein R ³ and E are as defined for the compound of formula (I) or (II) or liberated from a functional derivative of the compound of formula (I) by treatment with a solvolizing or hydrogenolytic agent and / or converting one or more R and / or R ² substituents of a compound of formula (I) to one or more other R and / or R ² substituents and / or converting a compound of formula (I) with a base or acid.

In the foregoing and hereinafter, the residues, or substituents R, R ¹ to R ⁷ , X, Y, A, Hal, E, X ¹ and X ² have the meanings given in the formulas I to VI, unless we are going to write a different report.

In the above formulas, the alkyl group is A

C 1 -C 6, preferably 1, 2, 3 or 4 carbon atoms. Preferred are methyl, ethyl, propyl, isopropyl, butyl, iso 6-butyl, sec- butyl or tert-butyl, and also pentyl,

1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethyl-butyl, 1- or

2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. Preferred alkenyl groups are vinyl or 1- or 2-propenyl or 1-butenyl and 1-pentenyl or 1-hexenyl. Preferred alkynyl groups include ethynyl, 1- or 2-propynyl, and 1-butynyl, 1-pentynyl or 1-hexynyl.

Hal is preferably fluorine, chlorine or bromine, but may also be iodine.

The R substituent derivable to a 3H-imidazo [4,5-c] pyridine (hereinafter 3H-IP) unit, particularly 2-ri-4- (thi) oxo-5-R @ ³ -6-R @ ⁴ -4,5 dihydro-3H-imidazo [4,5-c] pyridin-3-yl.

Ar is preferably phenyl, ο-, m- or ρ-tolyl, ο-, m- or ρ-ethylphenyl, ο-, m- or p-trifluoromethylphenyl, ο-, m- or p-methoxy. -phenyl, ο-, m- or ρ-ethoxyphenyl, ο-, m- or p- (difluoromethoxy) phenyl, ο-, m- or p- (trifluoromethoxy) phenyl- , ο-, m- or ρ-carboxyphenyl, ο-, m- or p-methoxycarbonylphenyl, ο-, m- or p- (ethoxycarbonyl) phenyl, ο-, or ρ-cyanophenyl, ο-, m- or ρ-nitrophenyl, ο-, m- or p-aminophenyl, ο-, m- or ρ-acetamidophenyl, ο-, m - or p- (trifluoroacetamido) -phenyl, ο-, τη- or p- (methylsulfonamido) -phenyl, ο-, m- or p- (trifluoromethylsulfonamido) -phenyl, or ο-, m- or p- (ΙΗ-5-tetrazolyl) phenyl.

Seven are preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-,

4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, and more preferably 1,2,3-triazol-1-, -4- or -5-yl, 2,4-triazol-1-, -3- or -5-yl, 1,2,3-oxadiazol-4- or -5-yl,

1.2.4-oxadiazol-3 or -5-yl, 1,3,4-thiadiazol-2 or -5-yl,

1.2.4-thiadiazol-3 or -5-yl, 2,1,5-thiadiazol-3 or -4-yl,

3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl; -, 2-,

3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- or 5 benzimidazolyl, 1-, 3-, 4-,

5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4- , 5-,

6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-, or 7-benzisothiazolyl, 4-, 5-, 6-, or 7-benz-2-1,3-oxadiazolyl; -, 4-, 5-,

6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-,

7- or 8-quinazolyl,

1H-1, 2-, -5, -6- or 3H-2, -3, -5, -6- or 1H-1, 2-, -4-, -6- or 3H-2, -3, -4-, -6- or

On the sign of the Week

7- or 8-cinnolyl, 2-, 4-, 5-, 6-,

-7-methylimidazo [4,5-b] pyridyl,

-7-methylimidazo [4,5-b] pyridyl,

-7-imidazo [4,5-c] pyridyl, or

-7-methylimidazo [4,5-c] pyridyl. is understood to mean those homologous units in which the heteroaromatic ring is substituted by one or more, preferably one or two, substituents A, preferably methyl and / or ethyl, such as 3-, 4- or 5-methyl-.

- 8 -2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-dimethyl-3-furyl, 3-, 4- or 5-methyl-2-thienyl; methyl-5-tert-butyl-2-thienyl,

2-, 4- or 5-methyl-3-thienyl, 2- or 3-methyl-1-pyrrolyl, 1-,

3-, 4- or 5-methyl-2-pyrrolyl, 3,5-dimethyl-4-ethyl-2-pyrrolyl, 2-, 4- or 5-methyl-1-imidazolyl, 4-methyl-5 pyrazolyl,

4- or 5-methyl-3-isoxazolyl, 3- or 5-methyl-4-isoxazolyl,

3- or 4-methyl-5-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4 or 5-methyl-2-thiazolyl, 4- or 5-ethyl-2-thiazolyl, 2- or

5-methyl-4-thiazolyl, 2- or 4-methyl-5-thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, 5- or 6-methyl-2-pyridyl, 2-, 4-, 5-, or 6-methyl-3-pyridyl; 2- or 3-methyl-4-pyridyl; 4-methyl-2-pyrimidinyl; 4,6-dimethyl-2-pyrimidinyl; , 5- or 6-methyl-4-pyrimidinyl, 2,6-dimethyl-4-pyrimidinyl, 3-, 4-, 5-, 6-, or 7-methyl-2-benzofuryl, 2-ethyl- 3-benzofuryl, 3-, 4-, 5-,

6- or 7-methyl-2-benzothienyl, 3-ethyl-2-benzothienyl, 1-, 2-,

4-, 5-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or 6-benzimidazolyl or 1-ethyl-5- or 6-benzimidazolyl.

Preferably R ^{1 is} straight-chain and preferably represents A or alkenyl, in each case C 3-6, preferably butyl, further propyl, pentyl or hexyl, allyl or 1-propenyl, and 1-butenyl, 1-pentenyl, 1-hexenyl, 1-propynyl, 1-butynyl, 1-pentynyl or 1-hexynyl.

The ^R2 substituent is preferably ΙΗ-5-tetrazolyl, further preferably COOH, COOCH3, COOC2H5, CN or -NHSO2CF3 group.

Preferably the alkyl moiety in R ³ is

-ch ₂ -.

• · «·

Accordingly, R ^{3 is} preferably r 5 -co-CH ₂ -, Ar-CO-CH ₂ -, Het-CO-CH ₂ - or Het-CH ₂ -.

Some preferred values for R ³ are: 2-oxopropyl, 2-oxobutyl, 3-methyl-2-oxobutyl, 3,3-dimethyl-2-oxobutyl, 3, 3,3-trifluoro-2-oxopropyl, 3,3,4,4,4-pentafluoro-2-oxobutyl, phenacyl (= 2-oxo-2-phenylethyl), ο- , m or ρ-methylphenacyl, ο-, m- or ρ-ethylphenacyl, ο-, m- or p- (trifluoromethyl) phenacyl, ο-, m- or ρ-methoxyphenacyl -, ο-, m- or ρ-ethoxyphenacyl, ο-, m- or p- (difluoromethoxy) phenacyl, ο-, m- or p- (trifluoromethoxy) phenacyl, ο -, m or p-carboxyphenacyl, ο-, m- or p- (methoxycarbonyl) phenacyl, ο-, m- or p-ethoxycarbonyl-phenacyl, ο-, m- or p- cyanophenacyl, ο-, m- or p-nitrophenacyl, ο-, m- or p-aminophenacyl-, ο-, m- or p-acetamidophenacyl-, ο-, m- or p-trifluoroacetamido-phenacyl, ο-, m- or p-methylsulfonamido-phenacyl, ο-, m- or p- (trifluoromethylsulfonamido) -phenacyl, o-, m- or p- - (1H-5-tetrazolyl) -phenacyl, 2-furoylmethyl, 2-theonylmethyl, picolinoylmethyl, nicotinoylmethyl, iso onicotinoylmethyl, pyrazine (carbonylmethyl) -, 2-,

4-, 5- or 6-pyrimidine (carbonylmethyl), 3- or 4-pyridazine-carbonylmethyl, benzofuran-2-, -3-, -4-, -5-, -6 - or -7- (carbonylmethyl), benzothiophene-2-, -3-, -4-, -5-, -6- or -7-carbonylmethyl), indole-2-, -3- , -4-, -5-, -6- or -7- (carbonylmethyl), 2- or 3-furylmethyl, 2- or 3-thienylmethyl,

5-isoxazolylmethyl, 5-methyl-3-isoxazolylmethyl, 2-, 3- or

4-pyridylmethyl, pyrazinylmethyl, 2-, 4-, 5- or 6-pyrimidinylmethyl, 3- or 4-pyridazinylmethyl, 2-, 3-, 4-,

5-, 6-, or 7-benzofurylmethyl, 2-, 3-, 4-, 5-, 6-, or 7 · · ·

- 10 benzothienylmethyl or 2-, 3-, 4-, 5-, 6- or 7-indolylmethyl groups. Of the substituted phenacyl groups, those substituted at the p-position are preferred.

Preferably R ⁴ is hydrogen, but may also be fluoro, chloro, bromo or iodo.

The ^R5 substituent is preferably 1, 2 or 3 carbon atoms, and is preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, or 3,3,3 trifluoro-propyl. If (I) compound contains two R ⁵ substituents may be the same or different.

Preferably X is absent or -NH-CO- or -CO-NH-.

The substituent Y is preferably oxygen, but may also be sulfur.

The compounds of formula I may have one or more chiral centers and may therefore exist in various optically active or optically inactive forms. The formula (I) includes all these forms.

Accordingly, the present invention is directed, in particular, to the preparation of compounds of formula I wherein at least one of the foregoing substituents has one of the preferred meanings indicated above. Some preferred classes of compounds of formula (I) may be expressed by the following formulas (Ia) to (II): Non-specifically substituted substituents have the meaning given to formula (I):

• · • »* ♦ · · *» * »· ·> ·· · ·· *

the (Ia) general wherein X missing; the (Ib) general wherein X is -NH-CO-; the (juice) general wherein X is -CO-NH-; the (Id) general wherein X is -O-CH (COOH) -; the (juice) general wherein X is -NH-CH (COOH) -; the (If) general wherein X is -NA-CH (COOH) -; the dg) general wherein X is -CH = C (COOH) -; the (Ih) general wherein X is -CH = C (COOH) -; the (Ii) general wherein X is -CH = C (ΙΗ-5-tetrazolyl) - -group.

Compounds of formula (Ia) are particularly preferred.

Further preferred are compounds of formulas (Ik) and (Ia) to (Iik), which correspond to compounds of formulas (I) and (Ia) to (III), wherein Y is as defined above with respect to the other substituents. oxygen;

compounds of formulas (II), (Ial) to (Ikl) and (laki) to (Iikl) which are represented by the following formulas (I), (Ia) to (Ik) and (lak) to (Iik) corresponding to compounds wherein R ⁴ is as defined above for hydrogen;

compounds of the formulas (Im), (Ilam) - (Ilm), (Ilam) - (Iklm) and (Iaklm) - (Iiklm), which are compounds of formulas (I), (Ia) - (II), (Ial). ) - (IIIc) and (Lac) - (IIIc), wherein R ² is -CN or ΙΗ-5-tetrazolyl as defined above.

Preferred among these compounds are those in which R ^{1 is} A is a substituent or alkenyl, each having 3 to 6 carbon atoms.

A further preferred embodiment of the compounds are those compounds of formula I and other compounds of the above formula wherein R ³ is (a) R ⁵ -CO-CH ₂ -, (b) Ar-CO-CH ₂ -, (c) Het-CO-CH ₂ -, (d) Het-CH ₂ - or (e) p-aminophenacyl.

A small group of preferred compounds corresponds to a compound of formula I wherein R is 2-butyl-4,5-dihydro-4-oxo-5-R ³ -3H-imidazo [4,5-c] pyridine -3-yl;

R ² is 5-tetrazolyl,

R ³ is 3,3-dimethyl-2-oxobutyl, phenacyl, 2- (2-benzofuryl) -2-oxoethyl or 2-thienylmethyl, and

X is missing.

The compounds of formula (I) and starting materials for their preparation are prepared by methods known per se, as described in the literature (e.g., in basic works such as Houben-Weyl, Methoden derorganchen Chemie, Georg-Thieme-Verlag, Stuttgart), and in particular, European Patent Nos. A2-0 430,709; and U.S. Patent 4,880,804, which use reaction conditions known and suitable for such reactions. Known variations not specifically enumerated herein may be employed in their execution.

If desired, the starting materials may also be prepared in situ by not isolating them from the reaction mixture, but immediately reacting them further to the compounds of formula (I).

The compounds of formula (I) are preferably obtained by reacting a compound of formula (II) with a compound of formula (III). This method of preparation is particularly suitable for the preparation of biphenyl derivatives of formula I (wherein X is absent).

In the compounds of formula (II), E is preferably chlorine, bromine or iodine, or a reactive, functionally modified hydroxy group such as a C 1-6 alkylsulfonyloxy group (preferably a methylsulfonyloxy group) or 6 -C 10 arylsulfonyloxy group (preferably phenyl or p-tolylsulfonyloxy group).

The reaction of the compound of formula (II) with the compound of formula (III) is conveniently carried out by converting the compound of formula (III) into a base, such as an alkali metal alcoholate such as sodium methylate or potassium tertiary acid. butylate, treated with an alcohol such as methanol or an alkali metal hydride such as sodium hydride or an alkali metal alcoholate in dimethylformamide (DMF), followed by treatment with an inert solvent such as an amide such as DMF or dimethylacetamide, or in a sulfoxide, such as dimethyl sulfoxide (DMSO), with a compound of formula II, conveniently at a temperature of -20 to 100 ° C, preferably 10 to 30 ° C. Suitable bases include alkali metal carbonates such as sodium carbonate or potassium carbonate or alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate.

The compounds of formula (I) may also be prepared by cyclization of compounds of formula (IV). The cyclization is conveniently carried out by heating with phosphoric acid, acetic acid or diglyme at a temperature of about 80-180 ° C, preferably 120-160 ° C.

The acid amides of formula I (X = -NH-CO- or -CO-NH-) may also be prepared by reacting a compound of formula V (or a reactive derivative) with a compound of formula VI (or a reactive derivative) .

As the reactive derivatives of the carboxylic acid derivatives of the formulas (V) and (VI) (X ¹ and X ² = COOH), the corresponding chlorides, bromides or anhydrides are preferably used. The reaction is conveniently carried out in the presence of an inert solvent such as a halogenated hydrocarbon such as dichloromethane, chloroform, trichloroethane or 1,2-dichloroethane or an ether such as tetrahydrofuran (THF) or dioxane at 0 to 150 ° C. , preferably between 20 and 80 ° C. When an acid halide is used, it is convenient to add a base such as a tertiary amine such as triethylamine, pyridine, or 4-dimethylaminopyridine.

Compounds of formula (I) may be prepared by reacting a compound of formula (VII) (which is otherwise represented by formula (I) but R ³ is hydrogen) with a compound of formula (VIII). The reaction is preferably carried out in an acid amide such as DMF, N-methylpyrrolidone, 1,3-dimethyl-2-oxo-hexahydropyrimidine or phosphoric acid hexamethyltriamide or in an alcohol such as methanol or tert-butanol, an ether, for example tetrahydrofuran or a halogenated hydrocarbon such as dichloromethane or mixtures thereof and / or an alkali metal alcoholate such as sodium methylate or potassium tert-butylate, an alkali metal hydride such as sodium or potassium hydride, an alkali metal carbonate such as sodium or potassium carbonate, an alkali metal bicarbonate such as sodium or potassium carbonate or a tertiary amine such as triethylamine or ethyl diisopropylamine in the presence of about -30 and 200 ° C, preferably 20 to 60 ° C.

They may also be prepared from their functional derivatives by liberating them by solvolysis (e.g., hydrolysis) or hydrogenolysis.

For example, a carboxylic acid of formula (I) wherein X is -O-CH (COOH), -NH-CH (COOH), -NA-CH (COOH), or -CH = C (COOH) can be prepared by the appropriate alkyl- ester saponification with, for example, sodium hydroxide or potassium hydroxide in aqueous solution, with or without the addition of an inert organic solvent such as methanol, ethanol, tetrahydrofuran or dioxane, or hydrogenolysis of the corresponding benzyl ester, e.g. palladium catalyst at a pressure of 1 to 200 bar at a temperature of 0 to 100 ° C in one of the inert solvents indicated above.

It is also possible by the methods described above to prepare compounds which are otherwise represented by the general formula (I) and which have a (protected) protected 1-position (or protected position) at the 1-position (or 2-position) of the 5-tetrazolyl group. Containing 2H) -5-tetrazolyl. Suitable protecting groups include, for example, triphenylmethyl, which may be cleaved with hydrochloric acid or formic acid in a solvent or solvent mixture, such as ether / dichloromethane / methanol; the 2-cyanoethyl group which may be cleaved with sodium hydroxide in a mixture of water and tetrahydrofuran; the p-nitrobenzyl group which may be cleaved by hydrogenation in ethanol in the presence of a Raney nickel catalyst (see European Patent Application A2-0 291 969).

The starting materials, in particular of formulas II, VI and VIII, are known in part. Those which are not known can be prepared by known methods analogous to known materials. Compounds of formula III (Y = 0) may be prepared, for example, by reacting a R 1 -COOH carboxylic acid with a compound of formula IX in the presence of phosphoric acid; during the reaction, the E substituent (preferably chlorine) is hydrolyzed to form compounds of formula (III) but containing hydrogen at the R ³ substituent, which is reacted with a compound of formula (VIII).

Compounds of formula (IV) may be prepared, for example, from compounds of formula (X) having amino groups with amino protecting groups (e.g., benzyl, A-O-CO- or benzyl).

protected by an oxycarbonyl group by reaction with a compound of formula II followed by cleavage of the protecting groups and reaction with an acid of formula R1-COOH or a functional derivative thereof; intermediates are generally not isolated, but compounds prepared in situ are used in the latter reaction.

Compounds of formula (V) may be prepared by reacting a compound of formula (III) with a benzyl chloride of the formula C ¹ -C ¹ -C ³ -Ch ³ -X ³ (wherein X ³ is a protected amino or carboxylic acid) and then followed by cleavage of the protecting group.

Compounds of formula (VII) may be prepared, for example, by reacting a compound of formula (III) but bearing a hydrogen atom at R ³ with a compound of formula (II).

Furthermore, it is also possible that a compound of general formula (I) into a different (I) is a compound of formula, to this end, one or more of the compounds of R and / or R ² substituents into another R and / or ^{R2-substituted} with, for example, a nitro group (e.g. hydrogenated in the presence of a Raney nickel or palladium on carbon catalyst in an inert solvent such as methanol or ethanol) is reduced to an amino group and / or a free amino and / or hydroxy group is functionally converted and / or a functionally converted amino and / or by hydrogenolysis and / or hydrolysis of a nitrile group to a carboxylic acid group or with derivatives of nitric hydrochloric acid such as sodium azide.

-methylpyrrolidone or trimethyl-6n-azide in toluene to form tetrazolyl.

For example, a free amino group may be acylated in a conventional manner with an acid chloride or anhydride or alkylated with an unsaturated or saturated alkyl halide, conveniently in a solvent such as dichloromethane or tetrahydrofuran and / or in the presence of a base such as triethylamine or pyridine. Between -60 and +30 ° C.

If desired, a functionally modified amino and / or hydroxyl group of a compound of formula (I) may be liberated by conventional solvolysis or hydrogenolysis. For example, a compound of formula (I) containing an -NHCOR ⁵ or a -COOA group may be converted to the corresponding compound of formula (I) which contains an amino or carboxyl group instead. For example, COOA groups may be saponified with sodium hydroxide or potassium hydroxide in water, water and tetrahydrofuran or water and dioxane at temperatures between 0 and 100 ° C.

The nitriles (I) of formula (for example, those wherein R ² is CN) as a tetrazole of formula by reacting a nitrogen-w hydrogen (I) (e.g., those in which R ² represents 1H-5-tetrazolyl). Preferably, the reaction is conducted with a trialkyltin azide, such as trimethyltin azide, in an inert solvent such as an aromatic hydrocarbon such as toluene, at a temperature between 20 and 150 ° C, preferably between 80 and 140 ° C, or with sodium azide. methyl-pyrrolidone

: ......: ···:: ··· • ·· · · ··· · · · · ·

- 19 to about 100 and a temperature between 200 ^e C.

A base of formula (I) can be converted into the corresponding acid addition salt with an acid. Acids that produce physiologically acceptable salts are primarily contemplated for this conversion. Inorganic acids such as sulfuric acid, nitric acid, halogenated acids such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid may be used, and organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, may be used. carboxylic, sulfonic or sulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acid, lauryl sulfuric acid. Non-physiologically acceptable salts, such as picrates, can be used in the isolation and / or purification of compounds of formula (I).

On the other hand, compounds of the formula I which contain a carboxyl or tetrazolyl group can be converted into the corresponding metal salts (in particular alkali metal or alkaline earth metal salts) or bases (for example sodium or potassium hydroxide or carbonate) or into the corresponding ammonium salts. Potassium salts of tetrazolyl derivatives are particularly preferred.

The novel compounds of formula (I) and their physiologically acceptable salts can be used in the preparation of pharmaceutical compositions by formulating the active compounds in an appropriate dosage form with at least one carrier or excipient and, if desired, one or more additional active ingredients. The compositions thus obtained can be used in human or veterinary medicine. Suitable carriers include organic or inorganic materials which are suitable for enteral (e.g., oral or rectal) or parenteral use or as inhalation sprays, and do not react with new compounds such as water, vegetable oils, benzyl alcohol, polyethylene glycol, glycerol triacetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose and starch, magnesium stearate, talc and cellulose. Tablets, dragees, capsules, syrups, juices or drops are particularly suitable for oral administration; of particular interest are lacquer coated tablets and capsules having a gastric acid-resistant coating or capsule shell. Suppositories, solutions for parenteral administration, preferably oily or aqueous solutions, suspensions, emulsions or implants are suitable for rectal administration. For use as inhalation sprays, sprays may be used which contain the active ingredient dissolved or suspended in a propellant mixture (e. G., Hydrofluorocarbons). In such a case, it is expedient to administer the active ingredient in micronized form and to administer one or more physiologically acceptable solvents, such as ethanol. Inhalation solutions may also be administered using standard inhalers. The novel compounds can also be lyophilized, and the lyophilizate thus obtained is, for example, ·

- 21 for use in the preparation of injection preparations. The compositions may be sterilized and / or may contain adjuvants such as preservatives, stabilizers and / or crosslinking agents, emulsifiers, salts for influencing the osmotic pressure, buffering agents, coloring agents and / or flavoring agents. If desired, they may also contain one or more additional active ingredients, such as one or more vitamins, diuretics or anti-inflammatory agents.

The substances of the invention are generally administered in an analogous manner to other known commercially available formulations, in particular analogous to those described in U.S. Patent 4,880,804, preferably in dosage units containing from 1 mg to 1 g, particularly preferably from 50 to 500 mg. added. The daily dose is preferably from about 0.1 to about 50 mg / kg body weight, in particular from about 1 to about 100 mg / kg body weight. The dosage to be used in each patient will be influenced by a variety of factors, such as the potency of the compound employed, the age, weight, general health, sex, diet, dosage regimen and route of administration, rate of excretion, combination and the severity of the disease. Oral administration is preferred.

As before and in the following, the temperature is given in ° C. In the following examples, the usual work-up is as follows: water is added, if necessary, adjusted to pH 2 to 10, depending on the composition of the final product, extracted with ethyl acetate or dichloromethane, the organic phase is separated with sodium dried over sulfate, evaporated and purified by chromatography on silica gel and / or crystallization.

The IP designation is imidazo [4,5-c] pyridine.

Example 1 (a) 2.71 g of 2-butyl-5- (2-furylmethyl) -4,5-dihydro-4-oxo-3H-IP [which, for valeric acid, is 3,4-diamino-2-chloro] by condensation with pyridine in the presence of polyphosphoric acid to 2-butyl-4,5-dihydro-4-oxo-1 (or 3) H-IP, with benzyl bromide in methanol, 3-benzyl-2-butyl-4 with CH 3 Na, By reaction of 5-dihydro-4-oxo-3H-IP with 2-furylmethyl chloride in DMF in the presence of K-tert-butylate, 3-benzyl-2-butyl-5- (2-furylmethyl) ) To a solution of 0.23 g of sodium in 20 ml of methanol is added dropwise over 15 minutes to a solution of this latter compound in 75 ml of methanol to give a hydrogenolytic cleavage of the benzyl group. . After stirring for 30 minutes at 20 ° C, the mixture was evaporated and the residue was dissolved in DMF (20 ml) and dropwise added at 0 ° C with 3.05 g of methyl 4'-bromomethyl-biphenyl-2-carboxylate. (Ha)] in DMF (10 mL) with stirring. The mixture was stirred at 20 ° C for an additional 16 h, then concentrated, worked up in the usual manner and chromatographed on silica gel to give 2-butyl-5- (2-furylmethyl) -4,5-dihydro-3- (2'-methoxy). -carbonyl-biphenylyl-4-methyl) -4-oxo-3H-IP is obtained.

(b) A mixture of 1 g of the methyl ester obtained in step (a) in aqueous 2N sodium hydroxide solution (12 ml) and methanol (48 ml) was refluxed for 2 hours and evaporated. The mixture was worked up in the usual manner (aqueous hydrogen chloride in dichloromethane was added until pH = 3) to give 2-butyl-5-. (2-Furylmethyl) -4,5-dihydro-3- (2'-carboxybiphenylyl-4-methyl) -4-oxo-3H-IP is obtained.

Example 2

In a manner analogous to Example 1, 2.87 g of 2-butyl-4,5-dihydro-4-oxo-5- (2-thienylmethyl) -3H-IP and 2.98 g of 3 p-bromomethylphenyl-2-phenylacrylonitrile [m.p. 178 DEG C .; By condensation of p-tolyl aldehyde with phenylacetonitrile in ethanol in the presence of sodium ethylate and bromination of the resultant 2-phenyl-3-p-tolylacrylonitrile (m.p. 65 ° C) with dichloromethane with N-bromosuccinimide. ], 2-Butyl-3- [p- (1-cyano-2-phenyl-vinyl) -benzyl] 4,5-dihydro-4-oxo-5- (2-thienylmethyl) -3H-IP win.

Example 3

1.02 g of valeric acid, 4.55 g of 4-amino-1,2-dihydro-2-oxo-3- [2 '- (ΙΗ-5-tetrazolyl) biphenyl-4-methylamino] -1- ( 2-thienylmethyl) pyridine [3-amino-4-benzylamino-1,2-dihydro-2-oxo-1- (2-thienylmethyl) pyridine] 4-bromomethyl-2'- reaction with cyano-biphenyl and the resulting 4-benzylamino-3- (2'-cyano-biphenylyl-4-methylamino) -1,2-dihydro-2-oxo-1- (2-thienylmethyl) ) pyridine with trimethyltin azide and the resulting 4-benzylamino-1,2-dihydro-2-oxo-3- [2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl -amino] -1- (2-thienylmethyl) pyridine is obtained by hydrogenolytic cleavage of the benzyl group] and 50 g of polyphosphoric acid are maintained at 140 ° C for 5 hours. Intermediate in situ 4-amino-1,2-dihydro-2-oxo-3- [N- [2 '- (? -5-tetrazolyl) biphenylyl-4-methyl-N-valerylamino] -1- ( 2-thienylmethyl) pyridine and 1,2-dihydro-224

-οχο-3- [2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methylamino] -1- (2-thienylmethyl) -4-valerylaminopyridine. The mixture was cooled, poured onto ice, basified with sodium hydroxide, and worked up in the usual manner. Thus, 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl] -5- (2-thienylmethyl) -3H-IP- mp 145 ° C.

Example 4

1.1 g of 3-p-aminobenzyl-2-butyl-4,5-dihydro-4-oxo-5- (2-thienylmethyl) -3H-IP [which is 2-butyl-4,5-dihydro By reaction of 4-oxo-5- (2-thienylmethyl) -3H-IP with p-nitrobenzyl bromide to give 2-benzyl-4,5-dihydro-3-p-nitrobenzyl-4 The mixture was prepared by hydrogenation of oxo-5- (2-thienylmethyl) -3H-IP], a mixture of 0.6 g of phthalic anhydride and 40 ml of trichloromethane was stirred for 16 hours at 20 ° C. Precipitated 2-butyl-3- [4- (o-carboxybenzamido) -benzyl] -4,5-dihydro-4-oxo-5- (2-thienylmethyl) -3H-IP is filtered.

Example 5

3.92 g of 3-p-aminobenzyl-2-butyl-4,5-dihydro-4-oxo-5- (2-thienylmethyl) -3H-IP, 3 ml of triethylamine, 0.5 g A mixture of 4-dimethylaminopyridine and 120 ml of dichloromethane was cooled to 5 ° C and 2.88 g of o-trifluoromethanesulfonamido-benzoyl chloride in 20 ml of dichloromethane were added dropwise. The mixture was stirred for another 16 hours at 20 ° C, then concentrated and worked up in the usual manner. Thus, 2-butyl-4,5-dihydro-4-oxo-5- (2-thienylmethyl) -3- [4- (o-trifluoromethanesulfonamido) -benzamidobenzyl] -3H-IP-t win.

Example 6

4.88 g of 2-butyl-3-p-carboxybenzyl-4,5-dihydro-5-p-nitro: ......: * ··: j · * · • * · · ··· · · · · · · ··· ···

- A mixture of 25-phenacyl-4-oxo-3H-IP, 12 g of thionyl chloride and 35 ml of trichloromethane was refluxed for 6 hours and then concentrated. The crude acid chloride obtained is freed from the thionyl chloride residue by repeated dissolution in toluene and then dissolved in 80 ml of tetrahydrofuran. This solution was added dropwise to a solution of 1.7 g of anthranilic acid and 0.8 g of sodium hydroxide in 100 ml of water. The mixture was stirred for 24 hours and then acidified to pH 5 with hydrochloric acid. After conventional work-up, 2-butyl-3- [p- (2-carboxyanilinocarbonyl) -benzyl] -4,5-dihydro-5-p-mnitro-phenacyl-4-oxo-3H-IP is obtained.

Example 7 (a) 3.1 g of 2-butyl-3- (2'-cyano-biphenylyl-4-methyl) -4,5-dihydro-4-oxo-3H-IP [m.p. 179-180 ° C Obtained by reacting 2-butyl-4,5-dihydro-4-oxo-1 (or 3) H-IP in potassium carbonate with 4'-bromomethyl-2-cyanobiphenyl in DMF] 35 ml A solution of DMF in DMF was stirred at 20 ° C with 1.25 g of potassium tert-butylate. After stirring for 45 minutes, 2.65 g of 2-thienylmethyl chloride dissolved in 25 ml of DMF are added dropwise. The mixture was stirred for an additional 16 hours at 20 ° C and worked up in the usual manner. to give 2-butyl-3- (2 ^{1-cyano-biphenylyl-4-methyl)} -4,5-dihydro-4-oxo-5- (2-thienylmethyl) -3H-IP is obtained, mp 63 - 64 ° C.

The following 2-butyl-3- (2'-cyanobiphenylyl-4-methyl) -4,5-dihydro-4-oxo-5-R ³ -3H-IP derivatives were prepared analogously.

Reagent

2-furylmethyl chloride

R ³ represents

-5- (2-furylmethyl) t • · · · · * ·· * «·« «·

- 26 5-isoxazolylmethyl bromide

5-methyl-3-isoxazolyl-methyl bromide

2-pyridylmethyl chloride

3-pyridylmethyl chloride

4-pyridylmethyl chloride

2- (2-furyl) -2-oxo-ethyl bromide

2- (2-Thienyl) -2-oxoethyl bromide bromo or chloroacetone phenacyl chloride or bromide o-methoxyphenacyl chloride 1-bromo-2-butanone 1-bromo-3-methyl-2 -butanone 1-bromo-3,3-dimethyl-2-butanone o-nitrophenacyl chloride m-nitrophenacyl chloride p-nitrophenacyl chloride 1-bromo-3,3,3-trifluoroacetone

1-Bromo-3,3,4,4,4-pentafluoro-2-butanone

2- (3-Pyridyl) -2-oxoethyl chloride p-difluoromethoxyphenacyl chloride

-5- (5-isoxazolylmethyl) -5- (5-methyl-3-isoxazolylmethyl) -5- (2-pyridylmethyl) -5- (3-pyridylmethyl) -5- (4 pyridylmethyl) -5- (2-furoylmethyl) -5- (2-tenoylmethyl) -5- (2-oxopropyl) -, m.p. 57 ° C -5-phenacyl, m.p. Mp .: 70 ° C -5-o-methoxyphenacyl, m.p. 93 ° C -5- (2-oxobutyl) -5- (3-methyl-2-oxobutyl) -5- (3 , 3-dimethyl-2-oxobutyl) m.p. 156 ° C -5-o-nitrophenacyl -5-m-nitrophenacyl-5-p-nitrophenacyl -5- (3,3,3 -trifluoro-2-oxopropyl) -5- (3,3,4,4,4-pentafluoro-2-oxobutyl) -5-nicotinoylmethyl-5-p-difluoromethoxyphenacyl27 ·· * · «·· * * ··· j ·· * ··· · · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · p · trifluoromethoxy-phenacyl chloride chloride

2- (2-benzofuryl) -2-oxo-ethyl bromide

-5-p-trifluoromethoxy-phenacyl-5-p-cyanophenacyl-5- [2- (2-benzofuryl) -2-oxoethyl] -, m.p. 95 ° C (b) 4.06 A mixture of (g) of the compound obtained in step (a), 20.6 g of trimethyltin azide and 200 ml of toluene is refluxed for 24 hours and then concentrated. The residue was taken up in 100 ml of methanolic hydrogen chloride, stirred for 2 hours at 20 ° C and worked up in a known manner (with a saturated solution of sodium chloride in dichloromethane). Chromatography using ethyl acetate / hexane (80:20) as eluent gave 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl] -5. (2-thienylmethyl) -3H-IP is obtained, m.p. 145 ° C.

Is obtained analogously prepared in the step (a) of 2'-cyano-biphenylyl-derivatives The following 2-butyl-4,5-dihydro-4-oxo-3- [2 ¹ - (ΙΗ-5-tetrazolyl) -bifenilil- 4-methyl] -5-R ³ -3H-IP derivatives:

R ³ represents

-5- (2-furylmethyl) -5- (5-isoxazolylmethyl) -5- (5-methyl-3-isoxazolylmethyl) -5- (2-pyridylmethyl) -5- (3- pyridylmethyl) -5- (4-pyridylmethyl) -5- (2-furoylmethyl) • · «

-5- (2-tenoylmethyl) -5- (2-oxopropyl) -, m.p. 154 ° C.

-5-phenacyl, m.p. 189 ° C

-5-o-methoxyphenacyl, m.p. 133 ° C

-5- (2-oxobutyl) -5- (3-methyl-2-oxobutyl) -5- (3,3-dimethyl-2-oxobutyl) -, m.p. 203 ° C.

-5-o-nitro-phenacyl-5-m-nitro-phenacyl-5-p-nitro-phenacyl-5- (3,3,3-trifluoro-2-oxo-propyl) -5- (3 , 3,4,4,4-pentafluoro-2-oxobutyl) -5-nicotinoylmethyl-5-p-difluoromethoxyphenacyl-5-p-trifluoromethoxyphenacyl-5-p -cyanophenacyl-5- [2- (2-benzofuryl) -2-oxoethyl], m.p. : 194 ° C.

Example 8 (a) In a manner analogous to Example 7, 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (2-triphenylmethyl-2H-5-tetrazolyl) biphenyl] reacting 4-ylmethyl] -3H-IP out with 2-thienylmethyl chloride obtained from 2-butyl-4,5-dihydro-4-oxo-5- (2-thienylmethyl) -3- [2 ¹ - (2-triphenylmethyl-2H-tetrazolyl) -biphenylyl-4-methyl] -3H-IP.

The following 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (2-triphenylmethyl-2H-5-tetrazolyl) -biphenyl-4-methyl] -5-R was prepared analogously. ³ -3H-IP derivatives:

• · · · · »· · * · *« • · · · ··· · ♦ · 4 ··

- 29 is R ³

-5- (2-furylmethyl) -5- (5-isoxazolylmethyl) -5- (5-methyl-3-isoxazolylmethyl) -5- (2-pyridylmethyl) -5- (3- pyridylmethyl) -5- (4-pyridyl) methyl-5- (2-furoyl) -5- (2-thenoyl) methyl-5- (2-oxopropyl)

-5-phenacyl,

5-o-methoxy-phenacyl,

5- (2-oxobutyl) -5- (3-methyl-2-oxobutyl) -5- (3,3-dimethyl-2-oxobutyl)

-5-p-nitro-phenacyl-5-m-nitro-phenacyl-5-p-nitrophenacyl-5- (3,3,3-trifluoro-2-oxopropyl) -

5- (3,3,4,4,4-pentafluoro-2-oxobutyl) -5-methyl-nicotinoyl-5-p-difluoromethoxy-5-phenacyl-p-trifluoromethoxy-phenacyl-5 phenacyl-p-cyano-5- [2- (2-benzofuryl) -2-oxoethyl] -.

(b) 1 g of the product of step (a) is dissolved in 60 ml of n-hydrogen chloride in dioxane, and the solution is stirred for 16 hours at 20 ° C, then concentrated and worked up in the usual manner. Thus, 2-butyl-4,5-dihydro-4-oxo-3- [2- (1H-5-tetrazolyl) biphenyl-4-methyl] -5- (2-thienylmethyl) -3H-IP we win.

Analogously, from the corresponding 2-triphenylmethyl-2H-5-tetrazolyl derivatives from step (a), the ΙΗ-5-tetrazolyl derivatives described in Example 7 (b) are prepared.

Example 9

Prepared in analogy to Example 7 from 2-butyl-3- (p-2-cyano-2-phenyl-vinylbenzyl) -4,5-dihydro-4-oxo-3H-IP [m.p. 160 ° C]. C; Prepared by reaction of 2-butyl-4,5-dihydro-4-oxo-1 (or 3) H-IP with 3-p-bromomethylphenyl-2-phenylacrylonitrile] 2-benzoyl-1-chloro by reaction with ethane

5- (2-Benzoyl-ethyl) -2-butyl-3- (p-2-cyano-2-phenyl-vinyl-benzyl) -4,5-dihydro-4-oxo-3H-IP.

Example 10

In a manner analogous to that described in Example 1 (b), 2-butyl-4,5-dihydro-3- [p- (α-methoxycarbonyl-benzyloxy) -benzyl] -4-oxo-5-phenacyl-3H. -IP [which is reacted with phenacyl bromide of 2-butyl-3-p-acetoxybenzyl-4,5-dihydro-4-oxo-3H-IP followed by hydrolysis of the resulting 5-phenacyl derivative and obtained by etherification of butyl 4,5-dihydro-3-p-hydroxybenzyl-4-oxo-5-phenacyl-3H-IP with methyl a-bromophenylacetic acid] by saponification of 2-butyl-3- [p- (α-oxy-carboxyphenyl) benzyl] -4,5-dihydro-4-oxo-5-phenacyl-3H-IP.

Example 11 g 2-Butyl-4,5-dihydro-5-p-nitrophenacyl-4-oxo-3- [2 '- (1H-5-tetrazolyl) biphenyl-4-methyl] -3H-IP A solution of 20 ml of methanol was hydrogenated in the presence of 0.3 g of 5% palladium-on-carbon at 20 ° C under normal pressure until the calculated amount of hydrogen was taken up. The catalyst is filtered off and the filtrate is evaporated to give 5-p-aminophenacyl-2-butyl-4,5-dihydro-4-oxo-3- [2 * - (5-tetrazolyl) biphenylyl-4-methyl ] -3H-IP is obtained.

In an analogous manner, the following 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl] is prepared by hydrogenation of the corresponding nitro compounds of Example 7b. 3H-IP derivatives:

5-p-amino-m-amino-fenacil5 phenacyl.

Example 12

A solution of 2.82 g of trifluoromethanesulfonic anhydride in 10 ml of dichloromethane is added dropwise at -50 to -60 [deg.] C., 5.5 g of 5-p-aminophenacyl-2-butyl-4,5-dihydro-4-ΟΧΟ- A solution of 3- [2 '- (--5-tetrazolyl) biphenylyl-4-methyl] -3H-IP and 1.01 g of triethylamine in 30 ml of dichloromethane. The mixture was allowed to warm to 20 ° C, poured into dilute acetic acid and worked up in the usual manner. Thus, 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (1H-tetrazolyl) -biphenyl-4-methyl] -5-p-trifluoromethanesulfonamido-phenacyl-3H-IP-t win.

In an analogous manner, the following 2-butyl-4,5-dihydro-4-oxo-3- [2 '- (tet-tetrazolyl) -biphenylyl-4-methyl] -3H-IP- is obtained by acylation of the amino derivatives of Example 11. derivatives: 5-o-trifluoromethanesulfonamido-phenacyl-5-m-trifluoromethanesulfonamido-phenylacetyl.

The following examples illustrate pharmaceutical compositions containing the active compounds of the formula (I) or salts thereof.

• ·

- 32 The Example

Pills and dragees

The following ingredients are compressed into tablets in the usual way and coated, if desired, with a standard sucrose-based dragee coating:

An active ingredient of the formula (I) 100 mg Microcrystalline cellulose 278.8 mg Lactose 110 mg corn starch 11 mg Magnet z ium-s z t ear pass 5 mg Fine-distribution silica 0.2 mg

Example B

Hard gelatine capsules

Standard two-piece hard gelatin capsules are filled with a mixture of:

An active ingredient of the formula (I) 100 mg Lactose 150 mg Cellulose 50 mg Magnesium ium stearate 6 mg

Example C

Soft gelatine capsules

Conventional soft gelatin capsules are filled with a mixture of 50 mg of active ingredient and 250 mg of olive oil each.

Example D

ampoules

A solution of 200 g of the active ingredient in 2 kg of 1,2-propanediol is made up to 10 liters with water and filled into ampoules so that each ampoule contains 200 mg of the active ingredient.

Claims (6)

An imidiazopyridine derivative of formula (I) wherein: R is a group of formula (I), R 1 is A substituted alkenyl or alkynyl group containing up to 6 carbon atoms, R ² is H, -COOH, -COOA, -CN, -NO 2, -NHCOR ⁵ , -NHSO 2 R ⁵ or -5-tetrazolyl, R ³ is R ⁵ -CO-alkyl, Ar-CO-alkyl, Het-CO-alkyl or Het-alkyl, the alkyl of which is in each case C 1-6, R ⁴ is hydrogen or halogen, R ⁵ is C 1 -C 6 alkyl, in which one or more hydrogen atoms may be replaced by fluorine atoms, X is absent or represents -NH-CO-, -CO-NH-, -O-CH (COOH), -NH-CH (COOH), -NA-CH (COOH), -CH = C (COOH), -CH = C (CN) or -CH = C- (-5-tetrazolyl) -, Y is oxygen or sulfur, A is C 1-6 alkyl, Ar is unsubstituted or -R ^5, -OR ^5, COOH, COOA, CN, -NO 2, -NH 2, -NHCOR ^5, -NHSO 2 R ⁵ or 5-tetrazolyl ΙΗ-monosubstituted phenyl; Seven is a five or six membered heteroaromatic group containing from 1 to 3 nitrogen, oxygen and / or sulfur atoms, which may be optionally fused to a benzene or pyridine ring, and Hal is fluorine, chlorine, bromine or iodine and salts thereof. 2. 2-Butyl-4,5-dihydro-5- (3,3-dimethyl-2-oxobutyl) -4-oxo-3- [2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl] -3H-imidazo [4,5-c] pyridine; 3. 2-Butyl-4,5-dihydro-4-oxo-5-phenacyl-3- [2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl] -3H-imidazo [4,5-c] ] pyridine. 4. 2-Butyl-4,5-dihydro-4-oxo-3- [2 '- (ΙΗ-5-tetrazolyl) -biphenyl-4-methyl] -5- (2-thienylmethyl) -3H-imidazo [4,5-c] pyridine. 5. 5- [2- (2-Benzofuryl) -2-oxoethyl] -2-butyl-4,5-dihydro-3- [2 '- (ΙΗ-5-tetrazolyl) biphenylyl-4-methyl] -4-oxo-3H-imidazo [4,5-c] pyridine. A process for the preparation of imidazopyridine derivatives of the formula I and their salts, wherein the substituents have the meaning given in claim 1, characterized in that (a) a compound of the formula II - wherein E is a chlorine, bromine or iodine atom or a hydroxyl group converted into a free or reactive derivative and R ² and X are as defined in claim 1 with a compound of formula (III) wherein R is Or (b) a compound of formula (IV): wherein R ⁶ is R ¹ -CO- or H and R ⁷ is H (when R ⁶ is R ¹ -CO-) or R ¹ -CO (if R ⁶ is H) and R ¹ , R ² , R ³ , R ⁴ , X and Y are as defined in claim 1, - a cyclizing agent, or (c) for the preparation of compounds of formula I wherein X is -NH-CO- or - CO-NH-, a compound of formula (V) - wherein X ¹ is amino or carboxyl and R is a compound of formula (VI) as defined in claim 1 or a reactive derivative thereof, wherein X ² is a carboxyl group (if X ¹ is an amino group) or an amino group (if X ¹ is a carboxyl group), R ² is as defined in claim 1, or a reactive derivative thereof, or (d) a compound of formula VII: wherein R ¹ , R ² , R ⁴ , X and Y are as defined in Claim 1, wherein R ³ is as defined in Claim 1, E is, in Step (a), a compound of Formula II or reacting a functional derivative of a compound of formula (I) with a solvolizing agent or hydrogenolytic reagent and / or one or more R and / or R ² substituents of a compound of formula (I) with one or more other R and / or R ^{2 is} converted and / or a base or acid of the formula I is converted into a salt thereof. 4. A process for the preparation of a pharmaceutical composition comprising a compound of the formula I as claimed in claim 1 or a physiologically acceptable acid addition salt thereof, wherein the substituents have the meaning given in claim 1. • · · The at least one solid, liquid or semi-liquid carrier and / or excipient as defined in claim 36 is formulated in a suitable dosage form. Pharmaceutical compositions comprising at least one compound of the formula I as claimed in claim 1 and / or a physiologically acceptable acid addition salt thereof - wherein the substituents have the meaning given in claim 1.